Direct and indirect evidence suggests muscarinic cholinergic systems are involved in depression. Rapid eye movement (REM) latency and neuroendocrine responses to cholinergic agonist administration are enhanced in adults with major depression. With the use of cholinergic agonists and antagonists, the involvement of muscarinic cholinergic systems in both adult and adolescent, depression will be delineated. Preliminary data with the muscarinic cholinergic antagonist scopolamine suggest that both adolescent and adult depressives respond comparably, but to a greater extent than normal age-matched controls, possible due to the hypoactivity of presynaptic cholinergic elements. Further, the data support the view that REM sleep and hypothalamic-pituitary-adrenal (HPA) axis abnormalities represent 'trait' and 'state' phenomena, respectively, At the preclinical level, preliminary data suggest that the "up-regulation" of muscarinic cholinergic systems involved in regulation of the HPA axis might not be due to a primary insult to muscarinic systems per se, but might be an adaptive response to "other" abnormalities. A greater understanding of the physiology and pathophysiology of muscarinic cholinergic systems in humans and animals, as revealed by the responses of REM latency in humans, and the HPA axis in both humans and animals to cholinergic challenges, will lead to findings that should help elucidate basic neurophysiologic mechanisms underlying depression, and have important clinical implications and applications to this major psychiatric disorder.